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Objective: Theory of mind (TOM), or "mentalizing," refers to the ability to attribute mental states to self and others. Inferring what people are thinking and feeling is an important aspect of human social interaction, and it is also an important aspect of both psychiatric diagnosis and treatment. The authors conducted a positron emission tomography (PET) study to examine the neural substrates of TOM, using a task that mimics real-life social interaction., Method: Thirteen healthy volunteers underwent [(15)O]H(2)O PET while performing an experimental task and a control task. During the experimental task they created a "story" about the mental state of a stranger whom they imagined encountering on a park bench. During the control task, they read aloud a story requiring no mental state attribution., Results: The TOM task activated an extensive neural network that included the medial frontal cortex, the superior frontal cortex, the anterior and retrosplenial cingulate, and the anterior temporal pole; most of these activations were limited to the left hemisphere. In addition, the largest activation was in the contralateral right cerebellum, as well as the anterior vermis., Conclusions: A language-based TOM task activated distributed brain regions that are important for representing mental states of the self and others, retrieving memory of personal experiences, and coordinating and monitoring the overall performance of the task. The activations in the medial frontal cortex replicate findings in previous TOM studies, while the activations in the cerebellum reinforce the growing evidence that the cerebellum performs cognitive functions in the human brain.

Objective: Schizophrenia is currently conceptualized as a disease of functional neural connectivity, leading to symptoms that affect aspects of mental activity, including perception, attention, memory, and emotion. The neural substrates of its emotional components have not been extensively studied with functional neuroimaging. Previous neuroimaging studies have examined medicated patients with schizophrenia. The authors measured regional cerebral blood flow (rCBF) during performance of a task that required unmedicated patients to recognize the emotional valence of visual images and to determine whether they were pleasant or unpleasant., Method: The authors examined rCBF in 17 healthy volunteers and 18 schizophrenia patients who had not received antipsychotic medications for at least 3 weeks during responses to pleasant and unpleasant visual stimuli. Areas of relative increases or decreases in rCBF were measured by using the [(15)O]H(2)O method., Results: When patients consciously evaluated the unpleasant images, they did not activate the phylogenetically older fear-danger recognition circuit (e.g., the amygdala) used by the healthy volunteers, although they correctly rated them as unpleasant. Likewise, the patients showed no activation in areas of the prefrontal cortex normally used to recognize the images as pleasant and were unable to recognize them as such. Areas of decreased CBF were widely distributed and comprised subcortical regions such as the thalamus and cerebellum., Conclusions: This failure of the neural systems used to support emotional attribution is consistent with pervasive problems in experiencing emotions by schizophrenia patients. The widely distributed nature of the abnormalities suggests the importance of subcortical nodes in overall dysfunctional connectivity.

Objective: Studies of patients experiencing their first episode of psychosis have demonstrated that they typically remain undiagnosed and untreated for 1-2 years. It has been postulated that prolonged untreated psychosis may have serious effects: poor response to neuroleptic medications, poor clinical outcomes, and direct neurotoxicity. This study investigated the relationships between duration of untreated initial psychosis and neurocognitive functioning and high-resolution imaging brain measurements., Method: A total of 156 subjects with DSM-IV schizophrenia, schizophreniform disorder, or schizoaffective disorder were evaluated during their first episode of psychosis. Measurements included nine domains of neurocognitive functioning, volumetric measures of total brain tissue, gray and white matter, and CSF, and measures of brain surface anatomy., Results: The mean duration of untreated initial psychosis was 74.3 weeks. Correlations between neurocognitive functioning, brain volumetric measurements, and surface anatomy measurements with duration of untreated initial psychosis were weak; none reached statistical significance. When the group was divided on the basis of median duration of untreated initial psychosis, there were again no significant differences between the groups with long and short duration of untreated initial psychosis except on two measures (verbal memory and cortical sulcal depth)., Conclusions: The absence of strong correlations suggests that untreated initial psychosis has no direct toxic neural effects. These results suggest that large-scale initiatives designed to prevent neural injury through early intervention in the prepsychotic or early psychosis phase may be based on incorrect assumptions that neurotoxicity or cognitive deterioration may be avoided. Nevertheless, early treatment is justified because it reduces suffering.

Objective: Whether chronicity of illness produces progressive neural abnormality is an important question in current schizophrenia research. Positron emission tomography (PET) offers an opportunity to visualize and measure blood flow in vivo to address this issue. The authors previously compared healthy volunteers with neuroleptic-naive patients experiencing their first episode of schizophrenia and reported that abnormalities in blood flow, including lower flow in prefrontal regions and higher flow in the thalamus and cerebellum, are present at the early stage of schizophrenic illness. The goal of the present study was to measure blood flow with PET in patients with chronic schizophrenia., Method: PET was used to examine regional cerebral blood flow (rCBF) in 30 patients with chronic schizophrenia and 30 normal comparison subjects. To determine if the patterns of flow abnormality in the patients with chronic schizophrenia were similar to those of patients experiencing their first episode of schizophrenia, the same cognitive condition was examined as in the earlier study. The patients with chronic schizophrenia in the current study had been neuroleptic-free for at least 3 weeks., Results: As in the authors' previous study, the chronically ill patients showed lower flow in prefrontal areas and higher flow in thalamic and cerebellar regions than normal comparison subjects, suggesting that a similar neural dysfunction occurs in both first-episode and chronic schizophrenia., Conclusions: rCBF abnormalities in patients with chronic schizophrenia are not due to chronicity of illness or the effects of medication. These results provide evidence that the primary neural abnormalities in schizophrenia may occur in cortical, cerebellar, and thalamic regions and that the dysfunction in these regions may explain the "loosening of associations" that Bleuler considered to be the fundamental cognitive phenotype of schizophrenia. These abnormalities can be reconceptualized as "cognitive dysmetria."

Objective: To assist in the development of a model for the psychopathology of emotions, the present study sought to identify the neural circuits associated with the evaluation of visual stimuli for emotional valence., Method: Seventeen healthy individuals were shown three sets of emotionally laden pictures carrying pleasant, unpleasant, and neutral content. While subjects evaluated the picture set for emotional valence, regional cerebral blood flow was measured with the use of [15O] water positron emission tomography. Subjective ratings of the emotional valence of the picture sets were recorded. Data were analyzed by comparing the images acquired during the neutral condition with the unpleasant and pleasant image sets and the unpleasant and pleasant conditions with each other., Results: Processing of pleasant stimuli was associated with increased blood flow in the dorsal-lateral, orbital, and medial frontal cortex relative to the unpleasant condition and in the cingulate, precuneus, and visual cortex relative to the neutral condition. Evaluation of unpleasant stimuli activated the amygdala, visual cortex, and cerebellum relative to the pleasant condition and the nucleus accumbens, precuneus, and visual cortex relative to the neutral condition., Conclusions: Observing and assigning emotional value to unpleasant stimuli produced activations in subcortical limbic regions, whereas evaluation of pleasant stimuli produced activations in cortical limbic areas. These findings are consistent with the notion of a subcortical and archaic danger recognition system and a system detecting pleasantness in events and situations that is phylogenetically younger, involving primarily the prefrontal cortex.

Objective: Whether cognitive function in schizophrenia deteriorates, improves, or remains stable is a crucial question. Few studies have examined the longitudinal stability of cognitive function and the relationship between cognitive performance and clinical symptoms over time in a cohort of well-treated patients with schizophrenia., Method: In the present study, 54 patients with first-episode and recent-onset schizophrenia completed a comprehensive cognitive test battery and were rated on symptom measures at index hospitalization and again after 5 years., Results: Performance IQ and full-scale IQ significantly improved, whereas verbal IQ did not change. Group performance improved on some of the neuropsychological tests, including the Circle A letter-cancellation task, free recall of logical memory test score, and the Wisconsin Card Sorting Test. Mean finger-tapping performance worsened over time, whereas performance on other neuropsychological tests did not change. Negative, psychotic, and disorganized symptoms significantly improved over the time period. Changes in negative symptoms were correlated with performance changes in verbal IQ and full-scale IQ but not performance IQ. Improvement in verbal cognition was observed when negative symptoms improved. Psychotic and disorganized symptom dimensions were not correlated with any IQ measure., Conclusions: These results indicate that in a cohort of young patients receiving neuroleptic treatment early in their illness, cognitive performance does not deteriorate--and may improve. Only one of the three symptom dimensions--negative--was associated with change in cognitive performance. This study supports the view that negative symptoms are associated with a poor long-term cognitive outcome and may be closely related to the primary cognitive deficit in schizophrenia.

Objective: This study explored the neural circuitry used during recall of unstructured verbal material in schizophrenic patients and healthy volunteer subjects., Method: The subjects were 13 healthy volunteers and 14 schizophrenic patients. All patients were free of medication, and all subjects were right-handed. Two experimental cognitive conditions were used: recall of novel and practiced word lists (two 15-item lists from the Rey Auditory Verbal Learning Test). Both active recall tasks were compared with an eyes-closed resting baseline condition. A nonparametric randomization test was used to determine within- and between-group differences in regional cerebral blood flow., Results: Performance on both the practiced and novel memory tasks was nonsignificantly different in the patients and control subjects. During the novel memory task, the patients showed decreased flow in the right anterior cingulate, right thalamus, and bilateral cerebellum (left greater than right) relative to the control subjects. When recalling the practiced word lists, the patients showed decreased flow in the left dorsolateral prefrontal cortex, bilateral medial frontal cortex, left supplementary motor area, left thalamus, left cerebellar regions, anterior vermis, and right cuneus., Conclusions: Patients with schizophrenia fail to activate cortical-cerebellar-thalamic-cortical circuitry during recall of both well-learned and novel word lists.

Objective: This study used positron emission tomography to examine two kinds of personal memory that are used in psychiatric evaluation: focused episodic memory (recall of past experience, employed in "taking a history") and random episodic memory (uncensored thinking about experience, examined during analytic therapy using free association). For comparison, a third memory task was used to tap impersonal memory that represents general information about the world ("semantic memory")., Method: Thirteen subjects were studied using the [15O]H2O method to obtain quantitative measurements of cerebral blood flow. The three conditions were subtracted and their relative relationships examined., Results: The random episodic condition produced activations in widely distributed association cortex (right and left frontal, parietal, angular/supramarginal, and posterior inferior temporal regions). Focused episodic memory engaged a network that included the medial inferior frontal regions, precuneus/retrosplenial cingulate, anterior cingulate, thalamus, and cerebellum. The use of medial frontal regions and the precuneus/retrosplenial cingulate was common to both focused and random episodic memory. The major difference between semantic and episodic memory was activation of Broca's area and the left frontal operculum by semantic memory., Conclusions: These results indicate that free-ranging mental activity (random episodic memory) produces large activations in association cortex and may reflect both active retrieval of past experiences and planning of future experiences. Focused episodic memory shares some components of this circuit (inferior frontal and precuneus), which may reflect the time-linked components of both aspects of episodic memory, and which permit human beings to experience personal identity, consciousness, and self-awareness.

Objective: Structural neuroimaging and neuropathological studies have demonstrated a variety of aspects of brain morphology that appear to distinguish schizophrenic patients from comparison subjects (diagnostic effects), a predominance of left-sided pathology (laterality effects), and a greater likelihood of brain abnormality among males (gender effects). However, findings have been inconsistent across studies, perhaps reflecting limited power due to small study group sizes. The goal of this study was to examine diagnostic, laterality, and gender effects of brain morphology as assessed by magnetic resonance imaging in a large, carefully evaluated group of schizophrenic and comparison subjects., Method: One hundred two patients with schizophrenia (DSM-III-R) (70 men and 32 women) and 87 normal comparison subjects, chosen to be equivalent to the patients in terms of familial socioeconomic background, underwent magnetic resonance imaging with a 1.5-tesla scanner. All regions of interest were outlined manually by an experienced technician on all slices in which they were visualized. Region of interest volumes were compared across groups, and age, sex, and stature were controlled., Results: Schizophrenic patients were found to have larger lateral and third ventricles and smaller thalamic, hippocampal, and superior temporal volumes than comparison subjects. No significant differences were demonstrated for intracranial, cerebral, cerebellar, temporal lobe, caudate nuclei, or temporal horn volumes. There were no significant Laterality by Diagnosis effects and no significant Gender by Diagnosis effects for any of the regions of interest., Conclusions: Many, but not all, of the hypotheses informed by earlier studies regarding diagnostic effects were confirmed, while hypotheses regarding gender and laterality interactions with diagnosis were not supported.

Objective: This study was designed to evaluate the relation between intelligence and a variety of measures of brain structure., Method: Magnetic resonance imaging scans were used to measure the volume of the intracranial cavity, cerebral hemispheres, lateral ventricles, temporal lobes, hippocampus, caudate, and cerebellum, as well as the overall volume of gray matter, white matter, and CSF, in 67 healthy, normal volunteers. Intelligence was measured with the Wechsler Adult Intelligence Scale--Revised., Results: Full-scale IQ was found to be significantly correlated with intracranial, cerebral, temporal lobe, hippocampal, and cerebellar volume but not with caudate and lateral ventricle volume. There were also significant correlations of full-scale, verbal, and performance IQ with overall gray matter volume but not with white matter or CSF volume. Gender differences were noted in the pattern and number of correlations between the volume of the brain and its subregions and full-scale, verbal, and performance IQ., Conclusions: The results suggest that the size of some cerebral structures may account for a significant, but modest, proportion of the variance in human intelligence.

The hypothesis that alexithymia reflects a functional disconnection between the two cerebral hemispheres was examined in 25 male combat veterans with posttraumatic stress disorder (PTSD). Multiple regression analysis revealed that the efficiency of interhemispheric communication, evaluated with a tactile finger localization task, was a significant predictor of the degree of alexithymia, as measured by the Toronto Alexithymia Scale, independent of PTSD severity and IQ. The PTSD subjects without alexithymia did not differ on the finger localization task from 10 male control subjects without alexithymia. These data suggest that at least some forms of alexithymia may be mediated by an interhemispheric communication deficit.